Preclinical testing of novel treatments in pancreas cancer - - PowerPoint PPT Presentation

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Apr 07, 2024 380 likes •470 views

Preclinical testing of novel treatments in pancreas cancer xenograft models xenograft models David W. Hedley MD Dept of Medical Oncology and Hematology and Division of Applied Molecular Oncology and Division of Applied Molecular Oncology

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Preclinical testing of novel treatments in pancreas cancer xenograft models xenograft models

David W. Hedley MD Dept of Medical Oncology and Hematology and Division of Applied Molecular Oncology and Division of Applied Molecular Oncology OCI/PMH

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Science, Sept 4, 2008

At the genomic level, all pancreatic cancers are

different. But they become similar if you think in terms

d e e t ut t ey beco e s a you t te s

f signaling pathways rather than individual genes

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Several genetic changes can activate the PI3-kinase pathway in pancreatic cancer PI3 kinase pathway in pancreatic cancer

only one is sensitive to EGFR inhibitors!

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We now have drugs to block signaling pathways where the upstream effectors converge where the upstream effectors converge

but how safe are they?

NVP-BEZ235

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Simulating clinical trials using primary pancreas cancer xenografts grown orthotopically cancer xenografts, grown orthotopically

Heart Liver

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“Clinical trial”testing BEZ235 in 5 pancreas cancer patients as orthotopic implants in mice cancer patients as orthotopic implants in mice

Effects of daily dosing with BEZ235

n tumour weights

H&E pAkt

OCIP16 OCIP16 OCIP17 OCIP17 OCIP18 OCIP19 OCIP21

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How far can you push chronic dosing with a PI3 kinase inhibitor? dosing with a PI3-kinase inhibitor?

Following acute single

g g dose, pAkt goes down, but recovers at 24 hr

In chronic dosing we still

In chronic dosing, we still find pAkt at the end of treatment

Mice lose weight at higher
Mice lose weight at higher

dose levels

You cannot have

100% inhibition of a major signaling pathway 100% of the pathway 100% of the time!

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Future Directions

Drugs that block major downstream pathways are

diff t f d th t bl k f t different from drugs that block surface receptors

Alternative dose schedules

is intermittent high dose better?

is intermittent high dose better?
are some cancers “addicted” to PI3-kinase?
if so, how do we identify them?

if so, how do we identify them?

How to combine with chemotherapy
How do we develop combinations of molecular-

How do we develop combinations of molecular- targeted agents?

Linking oncology with pancreatic cancer genomics